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WHO Technical Document of the Use of Non-Pharmaceutical Forms of Artemisia

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WHO Technical Document of the Use of Non-Pharmaceutical Forms of Artemisia Malaria Policy Advisory Committee Meeting 2–4 October 2019, Geneva, Switzerland Background document for Session 3 WHO technical document of the use of non-pharmaceutical forms of Artemisia October 2019 Introduction Research on the herbal remedies used in the past has led to the discovery of malaria treatments that have saved millions of lives. The powdered bark of the cinchona tree was used to treat malaria, initially in South America and later across the globe. Quinine was first isolated from cinchona tree bark in 1820, and the pure compound quickly demonstrated greater potency than the hot infusions of the bark. With the availability of the pure compound, appropriate dosage could be established and the first modern chemotherapeutic agent against malaria was born (1,2). Today, the most widely used antimalarial treatments, artemisinin-based combination therapies (ACTs), are produced using the pure artemisinin compound extracted from plant Artemisia annua. A full malaria treatment course with an ACT costs less than US$ 2 to procure. There are still ACTs available, capable of treating all malaria strains globally, despite artemisinin partial resistance in South East Asia and resistance to some of the partner drugs used in ACTs. However, for those in need in malaria-endemic countries, ACTs are not always available, are only available at high prices, or are of substandard quality. These difficulties are used as part of the argument in promoting Artemisia plant materials as affordable and self-reliant medicines against malaria. Traditional herbal remedies have several limitations, especially when they are utilized for treating potentially fatal diseases such as malaria. The main limitations are related to standardization of plant cultivation and preparation of formulations, dosages, quality assurance, and evidence of clinical safety and efficacy. The aim of this technical document is to review the evidence on the effectiveness of non- pharmaceutical forms of Artemisia and to discuss the limitations specific to these herbal remedies. The discovery of artemisinin The search for new antimalarial drugs was fuelled by the spread of resistance to the most widely used antimalarial drugs. Chloroquine was introduced in 1934 but was not in wide-scale use until the 1950s. Chloroquine resistance emerged around 1957 in two locations: South America and along the Cambodia–Thailand border. The resistance spread from the Cambodia–Thailand border areas throughout South-East Asia (3). During the Viet Nam–American war, the North Vietnamese government requested assistance from China to manage the chloroquine drug-resistant malaria that was affecting their military forces (4). In 1967, China launched Project 523 – a project aimed at finding new drugs for the treatment of malaria. The project involved 60 research organizations and more than 500 scientists (5). As part of the project, Chinese scientists examined ancient medical texts, reviewing more than 2000 recipes and testing extracts from more than 100 plants on rodent malaria parasites Plasmodium berghei. The plant This document was prepared as a pre-read for the meeting of the Malaria Policy Advisory Committee and is not an official document of the World Health Organization. WHO/CDS/GMP/MPAC/2019.10 A. annua was mentioned in several of the recipes, and the first extracts from A. annua did show antimalarial activity. However, this activity was highly variable, and the results were not satisfactory. A recipe from 341 A.D. for the treatment of fever, prescribed the juice of A. annua produced using cold water rather than tea produced through the traditional method of boiling herbs. There is no evidence that the Chinese used A. annua as a tea. Professor Tu Youyou, awarded the Nobel Prize in Medicine in 2015 for the discovery of artemisinin, realized that high temperatures could be causing the instability in the antimalarial activity and suggested that the leaves were likely the part of the plant with the most activity. Inspired by this, the Chinese researchers produced an extract using a low- temperature method with ether. This extract was shown to be highly efficacious against rodent and monkey malaria. The results led to a countrywide effort involving a large number of scientists from many institutions. The goal was to extract large quantities of the pure ingredient and determine its chemical structure and synthesis. The active antimalarial was identified in 1972 and named qinghaosu (or artemisinin in English) (6). Clinical trials initiated in 1972 confirmed the high antimalarial activity of artemisinin for both uncomplicated and severe malaria, with results published in English in 1979 (5,7). Despite recent progress in producing semi-synthetic artemisinin using yeast extraction, A. annua plants remain the main source of the drug (8). Artemisinin and its derivatives Artemisinin was identified as a sesquiterpene lactone peroxide and is essentially insoluble in water and oil. This, together with the high recrudescence rates observed, prompted the Chinese scientists to conduct further research on developing artemisinin derivatives. It was found that the peroxy group in artemisinin was essential for the antimalarial activity and had to be maintained in any derivatives to exhibit antimalarial effect. Treating artemisinin with sodium borohydride generated dihydroartemisinin, which was found to be an even more potent antimalarial than artemisinin. Dihydroartemisinin served as the basis for the development of oil- and water-soluble derivatives. Of the derivatives developed from dihydroartemisinin, Chinese researchers selected two compounds for larger scale trials based on their stability and high antimalarial efficacy: the oil-soluble artemether and the water-soluble artesunate (9–11). Pharmacokinetics and metabolism Several formulations and routes of administration for artemisinin have been tested. Although artemisinin does not dissolve in oil or water, the first trials included administration of artemisinin suspended in oil or water in addition to rectal and oral administration. Chinese researchers and others used a dose of 10 mg/kg of artemisinin per day, with the possibility of a loading dose of 20 mg/kg on the first day (12). Unlike artesunate or artemether, artemisinin is not metabolized to dihydroartemisinin, but acts as the primary antimalarial. Artemisinin is converted primarily into inactive metabolites, such as deoxyartemisinin and dihydrodeoxyartemisinin (13,14). The elimination half-life of artemisinin is approximately one to three hours (15,16). Following the administration of a drug, the total drug exposure across time depends both on the drug’s absorption and the elimination rate. For artemisinin, rapid but incomplete absorption has been observed. An early study found a relative bioavailability of 32% when comparing oral administration of artemisinin with intramuscular administration of artemisinin suspended in oil (17). Several artemisinin drugs are inducers of drug-metabolizing enzymes, which augment the drug’s clearance and lead to decreased drug plasma levels following repeated dosing (18). Studies have shown that artemisinin exhibits an auto-inductive effect on drug metabolism of an unusual magnitude (19). Artemether also undergoes auto-induction, but to a lesser extent than artemisinin (20,21). Artemisinin’s auto-induction results in a five- to seven-fold decrease in the artemisinin plasma concentration over five to seven days of administration (19). The overall induction capacity of a drug depends on the combined effect of the WHO technical document of the use of non-pharmaceutical forms of Artemisia| 2 parent drug and the drug metabolites. Unlike artemether, artemisinin metabolizes into at least one inducing metabolite, deoxyartemisinin. This helps explain why auto-induction persists for days after a single dose of artemisinin, despite artemisinin’s short elimination half-life (14,18,19,21–23). Consequently, when given repeatedly, the dose of artemisinin must be increased to achieve the same plasma concentrations. If not, the repeated dose could yield sub-therapeutic drug levels. Efficacy The potency of artemisinin and its derivatives has been evaluated in various in vitro experiments with different strains of P. falciparum. When investigating the drug concentration needed to inhibit 50% of the parasites’ activity, the IC50, artemisinin has consistently been found to be two to five times less potent than its derivatives dihydroartemisinin, artesunate and artemether (24,25). Consequently, higher doses of artemisinin are required to achieve the same antimalarial activity. In vivo drug efficacy is evaluated with respect to the proportion of patients in whom infection recurs within a defined period and, to a lesser extent, the speed at which symptoms resolve and parasitaemia declines. Artemisinin and its derivatives affect a broader range of the asexual stages of parasites than other antimalarials. As a result, artemisinin and its derivatives can quickly reduce the parasitaemia, leading to a rapid clinical response. However, already the earliest Chinese studies showed that if artemisinin is given orally for only three days, a high proportion of patients will have a recurrence of parasitaemia within 28 days. To prevent recurrent parasitaemia, seven days of treatment is needed when using artemisinin or an artemisinin derivative as a monotherapy (7,26). In practice, however, the rapid clinical response means that patients feel well after a few days of treatment, making adherence to the
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